The long-term objective of this revision application is to test hypotheses that overall anticholinergic (AC) medication exposure is associated with poor cognitive and physical performance outcomes in older adults using a novel and comprehensive assessment of AC exposure. The current paradigm is that AC medication use has reversible adverse effects on cognition, but this assumption has been challenged suggesting more detrimental permanent effects. The Specific Aims are: Aim 1: Determine whether cumulative and long-term AC burden is associated with: (1.a.) increased incidence of all-cause dementia or Alzheimer's disease (AD); and (1.b.) higher burden of neuropathological markers of dementia or AD (neuritic plaques, neurofibrillary tangles, amyloid angiopathy); Aim 2: Determine whether current anticholinergic burden is associated with greater decline in physical performance (gait speed, composite score of lower extremity function); Aim 3: Establish a system and infrastructure for data resource sharing through transfer of biospecimens and data using the established procedure of the National Cell Repository for Alzheimer's Disease (NCRAD) and continue our active collaboration with the Alzheimer's Disease Genetics Consortium (ADGC). This application will utilize the Adult Changes in Thought (ACT) study which is a 17 year longitudinal study of risk factors for incident dementia. ACT has enrolled over 4000 subjects from Group Health, a large integrated health maintenance organization. The ACT study is a unique data resource; it provides a community-based cohort with longitudinal objective assessments (every 2 years) of physical and cognitive function, autopsy data for examination of neuropathological correlates of dementia, and high quality exposure information from automated pharmacy records extending back 15 years prior to ACT study baseline. The availability of detailed automated pharmacy data will allow us to significantly improve the quantification of AC use over prior studies by our ability to examine cumulative long-term AC exposure and to quantify dose and duration of each AC medication. PUBLIC HEALTH RELEVANCE: Up to 25% of older adults are using AC drugs. Clinical practice would be significantly impacted if we find that long-term AC use is associated with a higher risk for dementia. It would provide a compelling reason to minimize long-term AC use and could pave the way to develop focused interventions to reduce AC drug use. This proposal will also enhance genetic and other data sharing from one of the most important ongoing studies of aging in the world